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The use of ephedrine and camphor in asymmetric Diels-Alder reactions.

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Due to the ever increasing demand for the production of enantiopure drugs and biologically active compounds, the study of asymmetric synthesis and the production of more efficient and cost effective methods of obtaining chiral compounds suggests that there are expanding opportunities for Organic Chemists in this field. Of the broad range of chiral technologies available today for the synthesis of even the most complex multi-centre chiral molecules, the use of chiral auxiliaries continues to remain an important means of obtaining single enantiomer chiral compounds. In this investigation, the imidazolidinone chiral auxiliary (i) was synthesised in order to determine its efficiency and ability to transfer chiral information in Diels-Alder cycloaddition reactions. The products of such reactions are extensively used in the synthesis of natural compounds and pharmaceutical drugs. The synthesis of the imidazolidinone auxiliary is described and mention is made of the fact that the starting materials are cheap and readily available in both enantiomeric forms. The pathway involves only a single reaction that is easily carried out in moderate yields of 60-65%. An adaptation of this auxiliary is the cyclohexyl derivative (ii) which was obtained in a single hydrogenation step of (i) in very high yields (98%). This was compared to the synthesis of the bornane-1O,2-sultam auxiliary (ii). Although the starting materials are also cheap and readily available, there are more reaction steps involved. The synthesis of the imidazolidinone auxiliary proved to be much more simple as well as more time and cost effective. The huge advantage of these auxiliaries is the fact that they are both crystalline which facilitates their purification and that of their derivatives. A possible deficiency of the imidazolidinone auxiliary and the bornane-1O,2-sultam auxiliary was the fact that substitution reaction yields with various a,b-unsaturated acyl chlorides were consistently low (<50%). A major by-product of the acylation reaction was a 'double-adduct' compound that severely affected the reaction yields. This was overcome by employing a new method of acylation developed during the course of this research. It involves the use of DABCO as base with reaction yields between 60 and 98%. In addition to this, reaction conditions were mild and work up procedures simple. The N-acylimidazolidinone auxiliary proved to be extremely successful in Diels-Alder reactions with cyclopentadiene With results equalling those obtained with the well known and highly publicised bornane-10,2-sultam auxiliary. The scope of the N-acylimidazolidinone auxiliary in these reactions included the use of a- and b- substituted dienophiles. Although reactions with a-methyl and b-methyl substituted dienophiles were successful, the auxiliary proved to be unreactive with b-phenyl and b,b-dimethyl substituted dienophiles. The scope of dienes used was extended to include the relatively less reactive isoprene and 2,3-dimethyl-l,3-butadiene. Only the former reacted successfully in Diels-Alder reactions with the N-acylimidazolidinone auxiliary. Crystallinity was imparted to all the products except for the cyclohexyl derivative whose cycloaddition adducts only solidified on standing. The Diels-Alder adducts were successfully cleaved under standard reaction conditions to give products with ee's ranging from 95:5 to 99:1. This investigation also includes the use of the tertiary amine, DABCO, as a catalyst in the Diels-Alder reaction with, specifically, the N-acryloylimidazolidinone chiral auxiliary. Most examples of Diels-Alder reactions involve the use of Lewis acids as a means of improving the rate and selectivity of Diels-Alder reactions. DABCO not only increased the reactivity of the N-acryloylimidazolidinone auxiliary towards cyclopentadiene, but selectivity was also observed. An explanation was put forward as to the mechanism of the reaction as well as to the source of selectivity. Selectivity was much more pronounced in Diels-Alder reactions with the N-acryloylimidazolidinone auxiliary than with the N-acryloylbornane-10,2-sultam auxiliary. It was predicted that DABCO catalysed reactions are amenable to large scale procedures. Due to the fact that the diastereomeric cycloadducts are easily purified by recrystallization or chromatography, and together with the practical advantages and mild reaction conditions this could render the DABCO methodology with the N-acryloylimidazolidinone auxiliary industrially viable.


Thesis (M.Sc.)-University of Natal, Pietermaritzburg, 1997.


Stereochemistry., Diels-Alder Reaction., Chemical reactions., Theses--Chemistry.